Body + Brain

13
Jun

Personalized Medicine Enters a New Era

This article was originally published on March 19, 2013. It was updated on June 13, 2013, with coverage of the U.S. Supreme Court ruling against gene patents along with reactions from scientists and researchers.

Sean Tavtigian felt incredible as he raced to work one brisk Monday morning in December 1995. He had spent the weekend conducting experiments and staring at a computer screen in his laboratory at Myriad Genetics, a genetic diagnostics company in Salt Lake City, Utah. Scientists at Myriad were competing in a race to discover the sequences of two genes, BRCA1 and BRCA2, that reveal a woman’s risk of hereditary breast and ovarian cancer. That morning, Tavtigian knew that he could solve the final piece of the puzzle just in time to win Myriad the rights over both genes.

In those days, the promise of personalized medicine was still a goal shimmering on the horizon. A deeper understanding of the genome, or even individual genes, as with BRCA1 and BRCA2, could give doctors the power to tailor treatments to their patients’ specific needs. Tavtigian and his colleagues at Myriad, along with thousands of scientists at universities, biotech companies, and pharmaceutical firms, sensed they were on the cusp of a medical revolution. But what they didn’t grasp was how the rush to patent genes could delay rather than hasten the adoption of personalized medicine.

Cutting an electrophoresis gel
A scientist cuts a gel after electrophoresis, a process which separates fragments of different lengths of DNA and is fundamental to genetic studies.

One year earlier, in 1994, Tavtigian and a team of scientists from Myriad and several universities had discovered BRCA1’s genetic sequence along with several mutations that can occur within it. A normal copy of the gene fights tumors, whereas women with a mutated version lack its protection—they have up to an 85% chance of developing breast cancer over the course of their lifetime, compared to a 12.7% chance in the general population. If women with the mutations could be identified before cancer set in, they might opt to lower their risk with preventative surgery. Researchers at the University of California, Berkeley had been the first to locate BRCA1 in the genome in 1990, and in 1991, a French team linked BRCA1 to ovarian cancer as well.

The whirlwind of discoveries continued with BRCA2. In 1994, a British team pinpointed its position in the genome. They planned soon after to publish the final element—the sequence of BRCA2.

“The U.K. team clearly had a piece of BRCA2 before anyone else,” Tavtigian says. They had filed a patent on the gene to the European Commission, and a premier science journal, Nature, had agreed to publish their results within a couple of weeks. When Tavtigian got wind of the plans, he sprung into action. To get the patent on BRCA2 in the United States, Myriad needed to post a sequence online before the British team’s publication went live.

By the Saturday before the paper came out, Tavtigian and his team had isolated four strands of DNA that he suspected could be strung together to form BRCA2. One strand contained a sequence that instructs other molecules to translate the DNA that follows into a protein. Another fragment included a sequence that signals the end of a gene. These pieces were like the cab and caboose of a train, while the two other fragments represented the boxcars in between. Tavtigian had the fragments, but he did not know how they linked to one another.

On Sunday, while Tavtigian stared at the data on his computer screen, something clicked. He had it. The next morning, Tavtigian recalls, he raced to work and informed his colleagues. “I told them that we could have a complete sequence in GenBank and a patent application filed in the U.S. before the U.K. team publishes their paper on Thursday.” If they did that, they’d have a good shot at being awarded the patents.

Just before midnight on Wednesday, December 20, Tavtigian and his colleagues uploaded the sequence of BRCA2 to the public database and filed a patent application with the U.S. Patent and Trademark Office. The next day, Nature published the U.K. team’s results. Myriad’s narrow margin over the U.K. team helped the firm win the U.S. patent on BRCA2. This was in addition to the patent they already held on BRCA1. Together, these patents have allowed the company to hold a complete monopoly on BRCA testing in the U.S.

“If the U.K.’s sequence had come out in Nature before we uploaded ours, Myriad would not be what it is today because they probably would not have had such a commanding patent,” Tavtigian says.

In a few weeks, on April 15, the U.S. Supreme Court will hear a case against Myriad’s patents, and gene patents in general, for the second time. Debate has swirled around Myriad’s patents since the key ones regarding BRCA1 and BRCA2 were first awarded in 1998, but the outcry has changed and intensified in the intervening years. Initially, the uproar focused on private companies using findings from dozens of federally funded researchers to gain exclusive rights over a gene. Now researchers and clinicians worry that gene patents compromise their ability to tailor treatments to individuals based on their DNA.

Genetic tests can reveal a lethal disease in an unborn baby, a risk of illness, or a dangerous reaction to a drug. They have already begun to usher in the era of personalized medicine, and technological advancements will continue to make the tests cheaper, faster, and ever more reliable. But recently, some researchers have hesitated to bring new and improved tests to the clinic for fear of infringing on a patented gene. It’s gotten to the point that Francis Collins, director of the National Institutes of Health, calls gene patents “an impediment to personalized medicine.”

Genetic Gold Rush

Collins first broached the topic of gene patents back in 1993 when he succeeded Nobel laureate James Watson, the co-discoverer of DNA’s structure, as head of the Human Genome Project. Collins oversaw the decade-long, $2.7 billion taxpayer-funded effort to sequence the human genome. From its onset, there were internal disagreements about whether patents would expedite or impede progress. In fact, Watson tells me that he left his position at the NIH in 1992, in part because of his strong feelings against them. “People were calling me anti-industry, although I have never been against industry,” Watson recalls. “I just thought it was crazy to patent genes.”

Francis Collins
Francis Collins was the head of the Human Genome Project in the late 1990s, when this portrait was taken. Currently, he is the director of the National Institutes of Health.

Collins, always the diplomat, took a more moderate approach to curb the gold rush. Together with Harold Varmus, NIH director at that time, Collins asked the USPTO to raise their standards for accepting a gene patent. They did, but only slightly. “People were just trying to claim every part of the genome, even in an absence of understanding a gene’s function,” Collins says. “And they were doing it in a way that may have been inhibitory rather than encouraging to future developments.”

While many patents on short fragments of DNA were struck down, patents on sequences encoding whole human genes have remained valid. Since 1990, scientists have patented an estimated 2,000 human genes. For researchers, companies, and clinicians, navigating that landscape can prove tricky. Some patent holders never enforce their claim or grant multiple companies a license. For example, in 1989, Collins and his colleagues placed a non-exclusive license on the CFTR gene linked with cystic fibrosis so other researchers could develop their own tests; as a result, at least 60 laboratories in the U.S. now assess the gene. But others, such as Myriad, use their temporary monopoly to full effect.

As soon as Myriad was granted patents on BRCA1 and BRCA2 in 1998, the company sent cease-and-desist letters to hospitals and small companies across the U.S. that were analyzing the genes. Myriad had developed a diagnostic test, named BRACAnalysis, that tested the genes, and they wanted to use their patents to guarantee the exclusivity of their test. Typically, companies leave academic researchers alone. However, when medical geneticists at university-affiliated hospitals sequence genes from participants in a study for their research, they take potential costumers away from companies like Myriad.

Harry Ostrer, a medical geneticist at Albert Einstein College of Medicine, received one of those letters. At the time, he was testing Jewish women for three common mutations in BRCA1 and BRCA2 in hopes of creating an efficient test of those variants. Previously, researchers reported that 1 in 50 Ashkenazi Jewish women carried one of these mutations, five times as many as in the general population. Unlike other researchers who heeded Myriad’s warning, Ostrer continued the study. “It was an annoying letter, and I ignored it,” he says. “But I was mindful of the fact that Myriad was looking over my shoulder.”

Harvard's Personal Genome Project is working to unravel environmental and genetic contributions to disease. Researchers there fear that if Myriad's patents are upheld, their work may be in violation.

Over the years, Ostrer and several others have criticized the business practices of companies like Myriad Genetics. In 2009, he and dozens of clinicians, patients, and geneticists became plaintiffs represented by the American Civil Liberties Union and the Public Patent Foundation in a case against Myriad Genetics. Researchers hope to eliminate the risk of genome-related patent lawsuits so that they can more efficiently develop and test patients’ genomes for thousands of disease-related mutations.

“Roughly 20% of the human genome is under patent,” says James Evans, a geneticist at the University of North Carolina at Chapel Hill and chair of a 2010 report on gene patents commissioned by the by the U.S. Department of Health and Human Services. “If these gene patents are enforced, it would have a chilling effect on potentially marvelous advancements in human care.”

Uncertainty

Genetic diagnostic tests have turned out to be more complex than geneticists anticipated in the 1990s. Back then, they thought a few mutations caused each heritable disease. Instead, a multitude of mutations with varying effects do. To learn how big of a risk these mutations pose, geneticists need to analyze as many DNA sequences as possible. This research is ongoing, and much of it is done behind industry walls. Take BRCA1, for example. The first mutations identified by researchers predispose women to breast cancer in a significant way, but there are several other, less common variants. Myriad’s database now contains sequences collected from more than a million women, giving them an advantage when predicting the risk those mutations pose.

Over the years, Myriad has updated their predictions for some of the less common mutations. But because their database is private, researchers are left guessing why Myriad’s position changed. In some cases, Myriad’s assessments differ from researchers’ results, which are based on laboratory experiments and a smaller, shared database. Rather than speak with Myriad about the data to clarify any discrepancies, many scientists lay low, says Robert Cook-Deegan, director of genome ethics, law, and policy at Duke University. That fear may not be entirely rational—there’s a large volume of academic research conducted on BRCA1 and BRCA2 without threats from Myriad—but the anxiety stifles scientific discourse. “Researchers really distrust Myriad,” Cook-Deegan says. “Asking Myriad whether what you’re doing is okay would be like calling up Darth Vader to say you’re traveling near the Death Star—would you do that?”

A Myriad spokesperson says that they ceased to contribute to a shared database for researchers in 2004 because of concerns that some clinicians would make incorrect predictions based on Myriad’s data. However, Cook-Deegan suspects that their decision is, in part, driven by the competitive advantage their huge database would give them when their patents expire.

Above all, geneticists worry that gene patents prevent new DNA technologies from reaching the clinic. With advanced sequencing technology, geneticists can now search for mutations in 40 genes related to cancer for less than the price of a BRACAnalysis test, which is estimated at $3,500. For about $2,000 more, researchers can sequence the genes that code for proteins, known as the exome. Or for roughly twice the price of Myriad’s test, all 22,000 genes in a person’s genome can be sequenced. But because of concerns about patent infringement, these tests usually do not reveal the status of BRCA1, BRCA2, and patented genes related to dozens of other diseases. Instead, doctors have to order multiple tests from various vendors, even though a single test is possible with current technologies. Expanded licensing could solve this issue, but that could significantly raise costs for clinicians.

“At the moment,” says Collins, the NIH director, “there is a good deal of uncertainty about whether individuals who wish to have their whole genome or exome sequenced are in legal jeopardy without paying a licensing fee to people who own patents on various pieces of the genome. If we end up with a $1,000 genome that comes with a $5,000 fee for royalties, that is not okay.”

According to the Myriad spokesperson, genome and exome sequencing can be done “without violating Myriad’s gene patent claims.” Some patent lawyers agree. Still, companies are wary. For example, Ambry Genetics does not include BRCA1 and BRCA2 in their cancer panels for fear of infringement. “I do not have an army of lawyers to fight patents,” says Charles Dunlop, CEO of Ambry Genetics. If Myriad’s patents are overturned in April, Dunlop says he would immediately add the genes to his tests.

Marilyn Li, a medical geneticist at Baylor College of Medicine, says the same of Baylor’s cancer panels. Another medical geneticist, Wendy Chung of Columbia University, cites a specific example of how convoluted gene testing is as a result of patents. Chung says a company that had sequenced one of her patient’s exomes was afraid to reveal the result of BRCA1 or BRCA2 in their official report. Instead, a technician anonymously called her to say she should send blood samples to Myriad to check their status. Chung would not reveal the company’s name.

“These gene patents make you wonder, why does some random person who once did something obvious hold the population of America ransom,” Dunlop says. “Why are they allowed to keep us from doing a better job?”

Patents for the People?

Hans Sauer, an intellectual property lawyer at the Biotechnology Industry Organization in Washington, D.C., says the value of patents outweighs the costs. Further, he says gene patents do not block innovation because modern sequencing methods do not infringe on them and that companies are unlikely to sue researchers despite rumors to the contrary. “At the end of the day,” Sauer says, “you need to ask, is it worth this inconvenience? What would be the price we’d pay to change patent law?” In other words, without gene patents, will gene-based therapies become a reality?

Twenty years ago, geneticists who favored patents hoped they would drive drug development. They looked forward to gene therapies that would reduce the damage caused by a defective gene by replacing it or counteracting its effects. Getting there would be expensive. Developing and testing a therapy in clinical trials could cost an estimated $1 billion, and given those steep costs, Sauer says the profits offered by gene patents may be essential to investors.

However, gene therapies have not worked thus far, whereas genetic tests have flourished. These tests do not require such heavy upfront investments. Tavtigian estimates that Myriad Genetics spent roughly $10 to $40 million on early research and development, and on the initial marketing of the BRACAnalysis test. In the past three years alone, BRACAnalysis, the company’s primary product, earned them more than $1 billion in revenue.

That might not be the case if gene patents didn’t exist. Collins says multiple laboratories would compete to provide high quality tests at a low price. What’s more, no single laboratory would own the bulk of the data on a single gene. The broad licensing of his patent on CFTR provides strong evidence of this outcome. Still, if he could travel back in time, Collins says he would try to deter his colleagues from patenting the gene.

Tavtigian, the scientist who helped Myriad secure the patents, is now a molecular geneticist at the University of Utah. His position on intellectual property has changed as well. “Patents might have been useful in stimulating diagnostic development in the 1990s, but the technology has improved to the point that we can evaluate a person’s genome for close to the cost of testing BRCA1 and BRCA2,” he says. “Now, these patents are standing in the way of progress in personalized medicine.”

In April, ACLU lawyers will ask Supreme Court judges to invalidate patents on human genes. Their case centers on a technical argument: Products of nature are not patentable by law, so the ACLU will try to show that DNA sequences are products of nature. Lawyers representing Myriad Genetics will argue the opposite by saying that researchers alter DNA by sequencing it. Myriad won the latest ruling in this case, issued last August by the Court of Appeals for the Federal Circuit.

Semantics may decide the case, but the heart of the debate is whether gene patents are preventing personalized medicine from reaching their potential in the clinic—one of the promises of the Human Genome Project back when it began. A decision by the Supreme Court could change that, or not.

Either way, it’s likely the fight over patents will continue. “There is a growing drumbeat of concern about whether the U.S. patent system serves the public interest,” says Shobita Parthasarathy, an expert on the politics of genetics and biotech patenting at the University of Michigan. “It might take time, but I think that eventually this outcry will lead to changes in policy.”

Epilogue

Eric Green is glowing. He was in the midst of cutting the tape for the June 13 opening of the first national exhibit on genomes, which celebrates the ten-year anniversary of sequencing the first human genome, when he learned that the Supreme Court rejected Myriad’s arguments, ruling that genes cannot be patented. Green is director of the NIH’s National Human Genome Research Institute and is quite familiar with the history of gene patents—he was involved with the Human Genome Project since its start in 1989. Today, he is visibly relieved, even ebullient.

“I am really happy with the decision because the essence of the genome project was to enable the scientific and medical community to use genomic information to advance human health,” he says. “And I get passionately angry at any barriers along the way.” To Green, gene patents were expensive toll booths on the highway toward personalized medicine.

Myriad’s patents on BRCA1 and BRCA2 stood for 15 years, and for the past couple of years, the company had successfully argued in appeals that isolated genes were no longer part of nature. It was an argument the Supreme Court didn’t buy. Specifically, the Supreme Court judges announced in their decision that the breast cancer genes BRCA1 and BRCA2 cannot be patented because genes are a product of nature and therefore not patentable by law. “Myriad did not create anything” with isolated DNA, Justice Clarence Thomas wrote for the court. “It found an important and useful gene, but separating that gene from its surrounding genetic material is not an act of invention.” An estimated 5,000 to 7,000 of human genes had been patented since 1982, when gene patents were first allowed. This decision now sets those genes free.

Before the decision, many scientists were worried that intellectual property concerns would prevent society from making the most of gene sequencing, a technology that delivers ever more accurate, faster, and cheaper ways of detecting a person’s risk for disease.

Lawrence Brody, a human geneticist at NHGRI, was all too familiar with those chilling effects. “We had a collaboration with a company that decided not to pursue a high-tech version of the BRCA1 test because they didn’t own the patent on the gene,” Brody says. “The real big impact [of the decision] is, going forward, people can now explore the genome, look for value, and test the genome without figuring out who owns which bit.”

Genetic diagnostic companies are celebrating the news as well. Before the decision, Ambry Genetics offered tests to assess the state of breast cancer genes, but excluded Myriad’s BRCA1 and BRCA2. Starting today, Ambry’s tests include them. “We were just waiting for this,” says Dunlop, Ambry’s CEO. “We are ready to go.”

Greg Lucier, CEO of Life Technologies, a biotech company, is similarly upbeat. “I think it’s a very positive ruling to both support the biotechnology therapeutics industry and the emerging diagnostic industry,” he says. Until today, when companies sequenced a person’s genome or exome, they also analyzed multiple genes linked to diseases, but they had to mask the results of genes that were patented by other companies. As a result, testing was more expensive and time-consuming. Lucier expects that to change. “We are now able to read across the genome and report out what we find with out the obstacles of patents in the way,” he says.

Biotech companies can still protect their work with patents. The Court clarified that “cDNA”—a synthetic version of DNA that lacks regions that do not encode proteins—remains patentable because it is not a product of nature. Most biotechnology companies patent cDNA strands that serve as the basis for their diagnostic tests and medicines. But those companies will face stiffer competition. Other firms can now develop better tests and therapies on the same underlying DNA, just using different cDNA.

For Brody and Green of the NHGRI, the decision marks the end of a long road. For years, they have discussed their concerns about gene patents with the solicitor general, who represents the U.S. government before the Supreme Court. Brody says this decision just makes sense. After all, he says, “Einstein did not get a patent on the laws of nature.”